Articles written in Journal of Biosciences

    • Rational design of type-IA receptor-derived cyclic peptides to target human bone morphogenic protein 2


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      Human bone morphogenetic protein 2 (BMP2) is a bone-growth regulatory factor involved in the formation of bone andcartilage, and has been recognized as an attractive therapeutic target for a variety of bone diseases and defects. Here, wereport successful design of a head-to-tail cyclic peptide based on crystal structure to target BMP2. Computational alaninescanning identifies two hotspot regions at the crystal complex interface of BMP2 with its type-IA receptor; promising one isstripped from the interface to derive a linear self-inhibitory peptide RPS2[r78-94] that covers residues 78–94 of the receptorprotein. Dynamics simulation and energetics analysis reveal that the peptide is highly flexible in isolated state and cannotspontaneously bind to BMP2. The RPS2[r78-94] peptide is further extended from its N- and C-termini until reaching twospatially vicinal residues 74 and 98 in the crystal structure of intact BMP2–receptor complex system, consequently resultingin a longer peptide RPS2[r74-98], which is then cyclized in a head-to-tail manner to obtain its cyclic counterpartcycRPS2[r74-98]. Computational analysis suggests that the cyclic peptide can well maintain in a conformation similar withits active conformation in complex crystal structure, exhibiting a smaller disorder and a larger potency than its linearcounterpart. Further assays confirm that the two linear peptides RPS2[r78-94] and RPS2[r74-98] are nonbinders of BMP2,whereas, as designed, the cyclic peptide cycRPS2[r74-98] can bind to BMP2 with a moderate affinity. The cyclic peptide isexpected as a lead molecular entity to develop new and potent peptide-based drugs for BMP2-targeted therapy.

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